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CellCept
(mycophenolate mofetil capsules)
(mycophenolate mofetil tablets)
®
CellCept Oral Suspension
(mycophenolate mofetil for oral suspension)
®
CellCept Intravenous
(mycophenolate mofetil hydrochloride for injection)
®
Rx only
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES AND SERIOUS
INFECTIONS
Use during pregnancy is associated with increased risks of first trimester pregnancy
loss and congenital malformations. Females of reproductive potential (FRP) must be
counseled regarding pregnancy prevention and planning (see WARNINGS and
PRECAUTIONS).
Immunosuppression may lead to increased susceptibility to infection and possible
development of lymphoma. Only physicians experienced in immunosuppressive
therapy and management of renal, cardiac or hepatic transplant patients should
prescribe CellCept. Patients receiving the drug should be managed in facilities
equipped and staffed with adequate laboratory and supportive medical resources.
The physician responsible for maintenance therapy should have complete
information requisite for the follow-up of the patient (see WARNINGS and
PRECAUTIONS).
DESCRIPTION
CellCept (mycophenolate mofetil) is the 2-morpholinoethyl ester of mycophenolic acid
(MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH)
inhibitor.
The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and
the following structural formula:
Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in
water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH
3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol.
The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The
1
pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the
phenolic group.
Mycophenolate mofetil hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose
Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.
CellCept is available for oral administration as capsules containing 250 mg of
mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a
powder for oral suspension, which when constituted contains 200 mg/mL mycophenolate
mofetil.
Inactive ingredients in CellCept 250 mg capsules include croscarmellose sodium,
magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells
contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium
lauryl sulfate, titanium dioxide, and yellow iron oxide.
Inactive ingredients in CellCept 500 mg tablets include black iron oxide, croscarmellose
sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400,
povidone (K-90), red iron oxide, talc, and titanium dioxide; may also contain ammonium
hydroxide, ethyl alcohol, methyl alcohol, n-butyl alcohol, propylene glycol, and shellac.
Inactive ingredients in CellCept Oral Suspension include aspartame, citric acid
anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate
dihydrate, sorbitol, soybean lecithin, and xanthan gum.
CellCept Intravenous is the hydrochloride salt of mycophenolate mofetil. The chemical
name for the hydrochloride salt of mycophenolate mofetil is 2-morpholinoethyl (E)-6(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4hexenoate hydrochloride. It has an empirical formula of C23H31NO7 HCl and a molecular
weight of 469.96.
CellCept Intravenous is available as a sterile white to off-white lyophilized powder in
vials containing mycophenolate mofetil hydrochloride for administration by intravenous
infusion only. Each vial of CellCept Intravenous contains the equivalent of 500 mg
mycophenolate mofetil as the hydrochloride salt. The inactive ingredients are polysorbate
80, 25 mg, and citric acid, 5 mg. Sodium hydroxide may have been used in the
manufacture of CellCept Intravenous to adjust the pH. Reconstitution and dilution with
5% Dextrose Injection USP yields a slightly yellow solution of mycophenolate mofetil,
6 mg/mL. (For detailed method of preparation, see DOSAGE AND
ADMINISTRATION).
CLINICAL PHARMACOLOGY
Mechanism of Action
Mycophenolate mofetil has been demonstrated in experimental animal models to prolong
the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel,
pancreatic islets, and bone marrow).
2
Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the
canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited
proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats,
as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in
combination with other immunosuppressive agents in these studies. Mycophenolate
mofetil has been demonstrated to inhibit immunologically mediated inflammatory
responses in animal models and to inhibit tumor development and prolong survival in
murine tumor transplant models.
Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed
to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive,
and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and
therefore inhibits the de novo pathway of guanosine nucleotide synthesis without
incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their
proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage
pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative
responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on
lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA
prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved
in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes
into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early
events in the activation of human peripheral blood mononuclear cells, such as the
production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of
these events to DNA synthesis and proliferation.
Pharmacokinetics
Following oral and intravenous administration, mycophenolate mofetil undergoes rapid
and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is
rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of
MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate
mofetil, can be measured systemically during the intravenous infusion; however, shortly
(about 5 minutes) after the infusion is stopped or after oral administration, MMF
concentration is below the limit of quantitation (0.4 µg/mL).
Absorption
In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil
relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area
under the plasma-concentration time curve (AUC) for MPA appears to increase in a doseproportional fashion in renal transplant patients receiving multiple doses of
mycophenolate mofetil up to a daily dose of 3 g (see Table 1).
Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of
mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant
patients. However, MPA Cmax was decreased by 40% in the presence of food (see
DOSAGE AND ADMINISTRATION).
3
Distribution
The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is
approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral
administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to
plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges
that are normally seen in stable renal transplant patients; however, at higher MPAG
concentrations (observed in patients with renal impairment or delayed renal graft
function), the binding of MPA may be reduced as a result of competition between MPAG
and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations
was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into
the cellular fractions of blood.
In vitro studies to evaluate the effect of other agents on the binding of MPA to human
serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA)
and MPAG (at ≥460 µg/mL with plasma proteins) increased the free fraction of MPA. At
concentrations that exceeded what is encountered clinically, cyclosporine, digoxin,
naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin
did not increase the free fraction of MPA. MPA at concentrations as high as 100 µg/mL
had little effect on the binding of warfarin, digoxin or propranolol, but decreased the
binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.
Metabolism
Following oral and intravenous dosing, mycophenolate mofetil undergoes complete
metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically
after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the
phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo,
MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of
the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral
administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)morpholine.
Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to
12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in
approximately a 40% decrease in the MPA AUC (largely as a consequence of lower
concentrations in the terminal portion of the profile). These observations suggest that
enterohepatic recirculation contributes to MPA plasma concentrations.
Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50%
increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal
insufficiency (see CLINICAL PHARMACOLOGY: Special Populations).
Excretion
Negligible amount of drug is excreted as MPA (<1% of dose) in the urine. Orally
administered radiolabeled mycophenolate mofetil resulted in complete recovery of the
administered dose, with 93% of the administered dose recovered in the urine and 6%
recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as
4
MPAG. At clinically encountered concentrations, MPA and MPAG are usually not
removed by hemodialysis. However, at high MPAG plasma concentrations
(>100 µg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as
cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the
drug (see OVERDOSAGE).
Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and
193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31)
mL/min following intravenous administration, respectively.
Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant
Patients
Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the
administration of mycophenolate mofetil given as single doses to healthy volunteers and
multiple doses to renal, cardiac, and hepatic transplant patients. In the early
posttransplant period (<40 days posttransplant), renal, cardiac, and hepatic transplant
patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax
approximately 32% to 44% lower compared to the late transplant period (3 to 6 months
posttransplant).
Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate
mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than
those observed after oral administration of a similar dose in the immediate posttransplant
phase. In hepatic transplant patients, administration of 1 g bid intravenous CellCept
followed by 1.5 g bid oral CellCept resulted in mean MPA AUC values similar to those
found in renal transplant patients administered 1 g CellCept bid.
5
Table 1
Pharmacokinetic Parameters for MPA [mean (±SD)]
Following Administration of Mycophenolate Mofetil to
Healthy Volunteers (Single Dose), Renal, Cardiac, and
Hepatic Transplant Patients (Multiple Doses)
Total AUC
(µg•h/mL)
Healthy Volunteers
1 g/oral
63.9
(single dose)
(±16.2)
(n=117)
Interdosing
Renal Transplant
Cmax
Interval
Patients (bid dosing)
Tmax
Dose/Route
AUC(0-12h)
Time After
(h)
(µg/mL)
Transplantation
(µg•h/mL)
5 days
1 g/iv
1.58
12.0
40.8
(±0.46)
(±3.82)
(±11.4)
(n=31)
(n=31)
(n=31)
6 days
1 g/oral
1.33
10.7
32.9
(±1.05)
(±4.83)
(±15.0)
(n=31)
(n=31)
(n=31)
Early (<40 days)
1 g/oral
1.31
8.16
27.3
(±0.76)
(±4.50)
(±10.9)
(n=25)
(n=25)
(n=25)
Early (<40 days)
1.5 g/oral
1.21
13.5
38.4
(±0.81)
(±8.18)
(±15.4)
(n=27)
(n=27)
(n=27)
Late (>3 months)
1.5 g/oral
0.90
24.1
65.3
(±0.24)
(±12.1)
(±35.4)
(n=23)
(n=23)
(n=23)
Interdosing
Cardiac Transplant
Cmax
Interval
Patients (bid dosing)
Tmax
Dose/Route
AUC(0-12h)
Time After
(h)
(µg/mL)
Transplantation
(µg•h/mL)
Early
1.5 g/oral
1.8
11.5
43.3
(Day before discharge)
(±1.3)
(±6.8)
(±20.8)
(n=11)
(n=11)
(n=9)
Late (>6 months)
1.5 g/oral
1.1
20.0
54.1a
(±0.7)
(±9.4)
(±20.4)
(n=52)
(n=52)
(n=49)
Interdosing
Hepatic Transplant
Cmax
Interval
Patients (bid dosing)
Tmax
Dose/Route
AUC(0-12h)
Time After
(h)
(µg/mL)
Transplantation
(µg•h/mL)
4 to 9 days
1 g/iv
1.50
17.0
34.0
(±0.517)
(±12.7)
(±17.4)
(n=22)
(n=22)
(n=22)
Early (5 to 8 days)
1.5 g/oral
1.15
13.1
29.2
(±0.432)
(±6.76)
(±11.9)
(n=20)
(n=20)
(n=20)
Late (>6 months)
1.5 g/oral
1.54
19.3
49.3
(±0.51)
(±11.7)
(±14.8)
(n=6)
(n=6)
(n=6)
a
AUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.
Dose/Route
Tmax
(h)
0.80
(±0.36)
(n=129)
Cmax
(µg/mL)
24.5
(±9.5)
(n=129)
6
Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five
mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent
to four 250 mg capsules.
Special Populations
Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the
administration of oral mycophenolate mofetil given as single doses to non-transplant
subjects with renal or hepatic impairment.
Table 2
Pharmacokinetic Parameters for MPA [mean (±SD)]
Following Single Doses of Mycophenolate Mofetil Capsules
in Chronic Renal and Hepatic Impairment
Renal Impairment
(no. of patients)
Healthy Volunteers
GFR >80 mL/min/1.73 m2
(n=6)
Mild Renal Impairment
GFR 50 to 80 mL/min/1.73 m2
(n=6)
Moderate Renal Impairment
GFR 25 to 49 mL/min/1.73 m2
(n=6)
Severe Renal Impairment
GFR <25 mL/min/1.73 m2
(n=7)
Hepatic Impairment
(no. of patients)
Healthy Volunteers
(n=6)
Alcoholic Cirrhosis
(n=18)
Tmax
(h)
0.75
(±0.27)
Cmax
(µg/mL)
25.3
(±7.99)
AUC(0-96h)
(µg•h/mL)
45.0
(±22.6)
1g
0.75
(±0.27)
26.0
(±3.82)
59.9
(±12.9)
1g
0.75
(±0.27)
19.0
(±13.2)
52.9
(±25.5)
1g
1.00
(±0.41)
16.3
(±10.8)
78.6
(±46.4)
Tmax
(h)
0.63
(±0.14)
0.85
(±0.58)
Cmax
(µg/mL)
24.3
(±5.73)
22.4
(±10.1)
AUC(0-48h)
(µg•h/mL)
29.0
(±5.78)
29.8
(±10.7)
Dose
1g
Dose
1g
1g
Renal Insufficiency
In a single-dose study, MMF was administered as capsule or intravenous infusion over 40
minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic
renal impairment [glomerular filtration rate (GFR) <25 mL/min/1.73 m2] was about 75%
higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m2). In
addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers
with severe renal impairment than in volunteers with mild renal impairment or healthy
volunteers, consistent with the known renal elimination of MPAG. No data are available
on the safety of long-term exposure to this level of MPAG.
Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers
(n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was
62.4 µg•h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe
chronic renal impairment has not been studied (see PRECAUTIONS: Patients with
Renal Impairment and DOSAGE AND ADMINISTRATION).
7
In patients with delayed renal graft function posttransplant, mean MPA AUC(0-12h) was
comparable to that seen in posttransplant patients without delayed renal graft function.
There is a potential for a transient increase in the free fraction and concentration of
plasma MPA in patients with delayed renal graft function. However, dose adjustment
does not appear to be necessary in patients with delayed renal graft function. Mean
plasma MPAG AUC(0-12h) was 2-fold to 3-fold higher than in posttransplant patients
without delayed renal graft function (see PRECAUTIONS: Patients with Renal
Impairment and DOSAGE AND ADMINISTRATION).
In 8 patients with primary graft non-function following renal transplantation, plasma
concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28
days. Accumulation of MPA was about 1-fold to 2-fold.
The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis.
Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG
(>100 µg/mL), hemodialysis removes only small amounts of MPAG.
Hepatic Insufficiency
In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy
volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected
by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers
and alcoholic cirrhosis patients within this study were compared. However, it should be
noted that for unexplained reasons, the healthy volunteers in this study had about a 50%
lower AUC as compared to healthy volunteers in other studies, thus making comparisons
between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of
hepatic disease on this process probably depend on the particular disease. Hepatic disease
with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a
single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment
(aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was
rapidly converted to MPA. MPA AUC was 44.1 µg•h/mL (±15.5).
Pediatrics
The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric
patients (ranging from 1 year to 18 years of age) receiving CellCept oral suspension at a
dose of 600 mg/m2 bid (up to a maximum of 1 g bid) after allogeneic renal
transplantation. The pharmacokinetic data for MPA is provided in Table 3.
8
Table 3
Mean (±SD) Computed Pharmacokinetic Parameters for MPA
by Age and Time After Allogeneic Renal Transplantation
Age Group
(n)
1 to <2 yr
1 to <6 yr
6 to <12 yr
12 to 18 yr
(6)d
(17)
(16)
(21)
1 to <2 yr
1 to <6 yr
6 to <12 yr
12 to 18 yr
(4)d
(15)
(14)
(17)
Tmax
(h)
Time
Dose Adjusteda
Cmax
(µg/mL)
Dose Adjusteda
AUC0-12
(µg•h/mL)
Early (Day 7)
3.03
1.63
0.940
1.16
(4.70)
(2.85)
(0.546)
(0.830)
10.3
13.2
13.1
11.7
(5.80)
(7.16)
(6.30)
(10.7)
22.5
27.4
33.2
26.3
(6.66)
(9.54)
(12.1)
(9.14)b
0.725
0.989
1.21
0.978
(0.276)
(0.511)
(0.532)
(0.484)
23.8
22.7
27.8
17.9
(13.4)
(10.1)
(14.3)
(9.57)
47.4
49.7
61.9
53.6
(14.7)
(18.2)
(19.6)
(20.3)c
0.604
0.869
1.12
1.09
(0.208)
(0.479)
(0.462)
(0.518)
25.6
30.4
29.2
18.1
(4.25)
(9.16)
(12.6)
(7.29)
55.8
61.0
66.8
56.7
(11.6)
(10.7)
(21.2)
(14.0)
Late (Month 3)
Late (Month 9)
1 to <2 yr
(4)d
1 to <6 yr
(12)
6 to <12 yr
(11)
12 to 18 yr
(14)
a
adjusted to a dose of 600 mg/m2
b
n=20
c
n=16
d
a subset of 1 to <6 yr
The CellCept oral suspension dose of 600 mg/m2 bid (up to a maximum of 1 g bid)
achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal
transplant patients receiving CellCept capsules at a dose of 1 g bid in the early
posttransplant period. There was wide variability in the data. As observed in adults, early
posttransplant MPA AUC values were approximately 45% to 53% lower than those
observed in the later posttransplant period (>3 months). MPA AUC values were similar
in the early and late posttransplant period across the 1 year to 18 year age range.
Gender
Data obtained from several studies were pooled to look at any gender-related differences
in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA
AUC(0-12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8)
µg•h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64)
µg/mL in the females. These differences are not of clinical significance.
Geriatrics
Pharmacokinetics in the elderly have not been studied.
CLINICAL STUDIES
Adults
The safety and efficacy of CellCept in combination with corticosteroids and cyclosporine
for the prevention of organ rejection were assessed in randomized, double-blind,
multicenter trials in renal (3 trials), in cardiac (1 trial), and in hepatic (1 trial) adult
transplant patients.
9
Renal Transplant
Adults
The three renal studies compared two dose levels of oral CellCept (1 g bid and 1.5 g bid)
with azathioprine (2 studies) or placebo (1 study) when administered in combination with
cyclosporine (Sandimmune ) and corticosteroids to prevent acute rejection episodes. One
study also included antithymocyte globulin (ATGAM ) induction therapy. These studies
are described by geographic location of the investigational sites. One study was
conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one
study was conducted in Europe, Canada, and Australia at a total of 21 sites.
®
®
The primary efficacy endpoint was the proportion of patients in each treatment group
who experienced treatment failure within the first 6 months after transplantation (defined
as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or
early termination from the study for any reason without prior biopsy-proven rejection).
CellCept, when administered with antithymocyte globulin (ATGAM ) induction (one
study) and with cyclosporine and corticosteroids (all three studies), was compared to the
following three therapeutic regimens: (1) antithymocyte globulin (ATGAM )
induction/azathioprine/cyclosporine/corticosteroids,
(2)
azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids.
®
®
CellCept, in combination with corticosteroids and cyclosporine reduced (statistically
significant at 0.05 level) the incidence of treatment failure within the first 6 months
following transplantation. Table 4 and Table 5 summarize the results of these studies.
These tables show (1) the proportion of patients experiencing treatment failure, (2) the
proportion of patients who experienced biopsy-proven acute rejection on treatment, and
(3) early termination, for any reason other than graft loss or death, without a prior biopsyproven acute rejection episode. Patients who prematurely discontinued treatment were
followed for the occurrence of death or graft loss, and the cumulative incidence of graft
loss and patient death are summarized separately. Patients who prematurely discontinued
treatment were not followed for the occurrence of acute rejection after termination. More
patients receiving CellCept discontinued without prior biopsy-proven rejection, death or
graft loss than discontinued in the control groups, with the highest rate in the CellCept
3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in
the CellCept 3 g/day group.
10
Table 4
Renal Transplant Studies
Incidence of Treatment Failure (Biopsy-proven Rejection or
Early Termination for Any Reason)
USA Studya
CellCept
2 g/day
(n=167 patients)
CellCept
3 g/day
(n=166 patients)
Azathioprine
1 to 2 mg/kg/day
(n=166 patients)
All treatment failures
31.1%
31.3%
47.6%
Early termination without
prior acute rejectionb
9.6%
12.7%
6.0%
Biopsy-proven rejection
episode on treatment
19.8%
17.5%
38.0%
CellCept
2 g/day
(n=173 patients)
CellCept
3 g/day
(n=164 patients)
Azathioprine
100 to 150 mg/day
(n=166 patients)
All treatment failures
38.2%
34.8%
50.0%
Early termination without
prior acute rejectionb
13.9%
15.2%
10.2%
Biopsy-proven rejection
episode on treatment
19.7%
15.9%
35.5%
CellCept
2 g/day
(n=165 patients)
CellCept
3 g/day
(n=160 patients)
Placebo
(n=166 patients)
All treatment failures
30.3%
38.8%
56.0%
Early termination without
prior acute rejectionb
11.5%
22.5%
7.2%
Biopsy-proven rejection
episode on treatment
17.0%
13.8%
46.4%
(N=499 patients)
Europe/Canada/
Australia Studyc
(N=503 patients)
Europe Studyd
(N=491 patients)
a
Antithymocyte globulin induction/MMF or azathioprine/cyclosporine/corticosteroids.
Does not include death and graft loss as reason for early termination.
c
MMF or azathioprine/cyclosporine/corticosteroids.
d
MMF or placebo/cyclosporine/corticosteroids.
b
The cumulative incidence of 12-month graft loss or patient death is presented below. No
advantage of CellCept with respect to graft loss or patient death was established.
Numerically, patients receiving CellCept 2 g/day and 3 g/day experienced a better
outcome than controls in all three studies; patients receiving CellCept 2 g/day
experienced a better outcome than CellCept 3 g/day in two of the three studies. Patients
11
in all treatment groups who terminated treatment early were found to have a poor
outcome with respect to graft loss or patient death at 1 year.
Table 5
Study
Renal Transplant Studies
Cumulative Incidence of Combined Graft Loss or Patient
Death at 12 Months
Control
CellCept
CellCept
(Azathioprine or
2 g/day
3 g/day
Placebo)
USA
8.5%
11.5%
12.2%
Europe/Canada/Australia
11.7%
11.0%
13.6%
Europe
8.5%
10.0%
11.5%
Pediatrics
One open-label, safety and pharmacokinetic study of CellCept oral suspension 600
mg/m2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was
performed at centers in the US (9), Europe (5) and Australia (1) in 100 pediatric patients
(3 months to 18 years of age) for the prevention of renal allograft rejection. CellCept was
well tolerated in pediatric patients (see ADVERSE REACTIONS), and the
pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid
CellCept capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). The rate
of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6
years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6
months was comparable to adults. The combined incidence of graft loss (5%) and patient
death (2%) at 12 months posttransplant was similar to that observed in adult renal
transplant patients.
Cardiac Transplant
A double-blind, randomized, comparative, parallel-group, multicenter study in primary
cardiac transplant recipients was performed at 20 centers in the United States, 1 in
Canada, 5 in Europe and 2 in Australia. The total number of patients enrolled was 650; 72
never received study drug and 578 received study drug. Patients received CellCept 1.5 g
bid (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with
cyclosporine (Sandimmune or Neoral ) and corticosteroids as maintenance
immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion
of patients who, after transplantation, had at least one endomyocardial biopsy-proven
rejection with hemodynamic compromise, or were retransplanted or died, within the first
6 months, and (2) the proportion of patients who died or were retransplanted during the
first 12 months following transplantation. Patients who prematurely discontinued
treatment were followed for the occurrence of allograft rejection for up to 6 months and
for the occurrence of death for 1 year.
®
®
(1) Rejection: No difference was established between CellCept and azathioprine (AZA)
with respect to biopsy-proven rejection with hemodynamic compromise.
12
(2) Survival: CellCept was shown to be at least as effective as AZA in preventing death
or retransplantation at 1 year (see Table 6).
Table 6
a
Rejection at 6 Months/Death or Retransplantation at 1 Year
All Patients
Treated Patients
AZA
N = 323
CellCept
N = 327
AZA
N = 289
CellCept
N = 289
Biopsy-proven rejection with
hemodynamic compromise at
6 monthsa
121 (38%)
120 (37%)
100 (35%)
92 (32%)
Death or retransplantation at
1 year
49 (15.2%)
42 (12.8%)
33 (11.4%)
18 (6.2%)
Hemodynamic compromise occurred if any of the following criteria were met:
pulmonary capillary wedge pressure ≥20 mm or a 25% increase; cardiac index
<2.0 L/min/m2 or a 25% decrease; ejection fraction ≤30%; pulmonary artery oxygen
saturation ≤60% or a 25% decrease; presence of new S3 gallop; fractional shortening
was ≤20% or a 25% decrease; inotropic support required to manage the clinical
condition.
Hepatic Transplant
A double-blind, randomized, comparative, parallel-group, multicenter study in primary
hepatic transplant recipients was performed at 16 centers in the United States, 2 in
Canada, 4 in Europe and 1 in Australia. The total number of patients enrolled was 565.
Per protocol, patients received CellCept 1 g bid intravenously for up to 14 days followed
by CellCept 1.5 g bid orally or azathioprine 1 to 2 mg/kg/day intravenously followed by
azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral ) and
corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose
of azathioprine on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and
1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints
were: (1) the proportion of patients who experienced, in the first 6 months
posttransplantation, one or more episodes of biopsy-proven and treated rejection or death
or retransplantation, and (2) the proportion of patients who experienced graft loss (death
or retransplantation) during the first 12 months posttransplantation. Patients who
prematurely discontinued treatment were followed for the occurrence of allograft
rejection and for the occurrence of graft loss (death or retransplantation) for 1 year.
®
Results
In combination with corticosteroids and cyclosporine, CellCept obtained a lower rate of
acute rejection at 6 months and a similar rate of death or retransplantation at 1 year
compared to azathioprine.
13
Table 7
Rejection at 6 Months/Death or Retransplantation at 1 Year
AZA
CellCept
N = 287
N = 278
Biopsy-proven, treated rejection
at 6 months (includes death or
retransplantation)
137 (47.7%)
107 (38.5%)
Death or retransplantation at 1 year
42 (14.6%)
41 (14.7%)
INDICATIONS AND USAGE
Renal, Cardiac, and Hepatic Transplant
CellCept is indicated for the prophylaxis of organ rejection in patients receiving
allogeneic renal, cardiac or hepatic transplants. CellCept should be used concomitantly
with cyclosporine and corticosteroids.
CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral
suspension. CellCept Intravenous should be administered within 24 hours following
transplantation. CellCept Intravenous can be administered for up to 14 days; patients
should be switched to oral CellCept as soon as they can tolerate oral medication.
CONTRAINDICATIONS
Allergic reactions to CellCept have been observed; therefore, CellCept is contraindicated
in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any
component of the drug product. CellCept Intravenous is contraindicated in patients who
are allergic to Polysorbate 80 (TWEEN).
WARNINGS
(see boxed WARNING)
Embryofetal Toxicity
Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant
female. Use of MMF during pregnancy is associated with an increased risk of first
trimester pregnancy loss and an increased risk of congenital malformations, especially
external ear and other facial abnormalities including cleft lip and palate, and anomalies of
the distal limbs, heart, esophagus, kidney and nervous system (see PRECAUTIONS:
Pregnancy).
Pregnancy Exposure Prevention and Planning
Females of reproductive potential must be made aware of the increased risk of first
trimester pregnancy loss and congenital malformations and must be counseled regarding
pregnancy prevention and planning.
For recommended pregnancy testing and
contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and
Planning).
14
Lymphoma and Malignancy
Patients receiving immunosuppressive regimens involving combinations of drugs,
including CellCept, as part of an immunosuppressive regimen are at increased risk of
developing lymphomas and other malignancies, particularly of the skin (see ADVERSE
REACTIONS). The risk appears to be related to the intensity and duration of
immunosuppression rather than to the use of any specific agent.
As usual for patients with increased risk for skin cancer, exposure to sunlight and UV
light should be limited by wearing protective clothing and using a sunscreen with a high
protection factor.
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving
CellCept (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of
renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS).
In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148
patients) have been observed (see ADVERSE REACTIONS).
Combination with Other Immunosuppressive Agents
CellCept has been administered in combination with the following agents in clinical
trials: antithymocyte globulin (ATGAM ), OKT3 (Orthoclone OKT 3), cyclosporine
(Sandimmune , Neoral ) and corticosteroids. The efficacy and safety of the use of
CellCept in combination with other immunosuppressive agents have not been
determined.
®
®
®
®
Serious Infections
Patients receiving immunosuppressants, including CellCept, are at increased risk of
developing bacterial, fungal, protozoal and new or reactivated viral infections, including
opportunistic infections. These infections may lead to serious, including fatal outcomes.
Because of the danger of oversuppression of the immune system which can increase
susceptibility to infection, combination immunosuppressant therapy should be used with
caution (see ADVERSE REACTIONS).
New or Reactivated Viral Infections
Polyomavirus associated nephropathy (PVAN), JC virus associated progressive
multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation
of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with
immunosuppressants, including CellCept. Reduction in immunosuppression should be
considered for patients who develop evidence of new or reactivated viral infections.
Physicians should also consider the risk that reduced immunosuppression represents to
the functioning allograft.
PVAN, especially due to BK virus infection, is associated with serious outcomes,
including deteriorating renal function and renal graft loss (see ADVERSE
REACTIONS: Postmarketing Experience). Patient monitoring may help detect
patients at risk for PVAN.
15
PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion,
cognitive deficiencies, and ataxia. Risk factors for PML include treatment with
immunosuppressant therapies and impairment of immune function (see ADVERSE
REACTIONS: Postmarketing Experience). In immunosuppressed patients, physicians
should consider PML in the differential diagnosis in patients reporting neurological
symptoms and consultation with a neurologist should be considered as clinically
indicated.
The risk of CMV viremia and CMV disease is highest among transplant recipients
seronegative for CMV at time of transplant who receive a graft from a CMV seropositive
donor. Therapeutic approaches to limiting CMV disease exist and should be routinely
provided. Patient monitoring may help detect patients at risk for CMV disease.
Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring
infected patients for clinical and laboratory signs of active HBV or HCV infection is
recommended.
Neutropenia
Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 103/µL] developed in up to
2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients
receiving CellCept 3 g daily (see ADVERSE REACTIONS). Patients receiving
CellCept should be monitored for neutropenia (see PRECAUTIONS: Laboratory
Tests). The development of neutropenia may be related to CellCept itself, concomitant
medications, viral infections, or some combination of these causes. If neutropenia
develops (ANC <1.3 x 103/µL), dosing with CellCept should be interrupted or the dose
reduced, appropriate diagnostic tests performed, and the patient managed appropriately
(see DOSAGE AND ADMINISTRATION). Neutropenia has been observed most
frequently in the period from 31 to 180 days posttransplant in patients treated for
prevention of renal, cardiac, and hepatic rejection.
Patients receiving CellCept should be instructed to report immediately any evidence of
infection, unexpected bruising, bleeding or any other manifestation of bone marrow
depression.
Pure Red Cell Aplasia (PRCA)
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with
CellCept in combination with other immunosuppressive agents. The mechanism for
mycophenolate mofetil induced PRCA is unknown; the relative contribution of other
immunosuppressants and their combinations in an immunosuppression regimen are also
unknown. In some cases, PRCA was found to be reversible with dose reduction or
cessation of CellCept therapy. In transplant patients, however, reduced
immunosuppression may place the graft at risk.
CAUTION: CELLCEPT INTRAVENOUS SOLUTION MUST NOT
ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION.
BE
16
PRECAUTIONS
Pregnancy Exposure Prevention and Planning
Females of reproductive potential must be made aware of the increased risk of first
trimester pregnancy loss and congenital malformations and must be counseled regarding
pregnancy prevention and planning.
Females of reproductive potential include girls who have entered puberty and all women
who have a uterus and have not passed through menopause. Menopause is the permanent
end of menstruation and fertility. Menopause should be clinically confirmed by a
patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12
months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or
medical therapy) or 2) postsurgical from a bilateral oophorectomy.
Pregnancy Testing
To prevent unplanned exposure during pregnancy, females of reproductive potential
should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL
immediately before starting CellCept. Another pregnancy test with the same sensitivity
should be done 8 to 10 days later. Repeat pregnancy tests should be performed during
routine follow-up visits. Results of all pregnancy tests should be discussed with the
patient.
In the event of a positive pregnancy test, females should be counseled with regard to
whether the maternal benefits of mycophenolate treatment may outweigh the risks to the
fetus in certain situations.
Contraception
Females of reproductive potential taking CellCept must receive contraceptive counseling
and use acceptable contraception (see Table 8 for acceptable contraception methods).
Patients must use acceptable birth control during entire CellCept therapy, and for 6 weeks
after stopping CellCept, unless the patient chooses abstinence (she chooses to avoid
heterosexual intercourse completely).
Patients should be aware that CellCept reduces blood levels of the hormones in the oral
contraceptive pill and could theoretically reduce its effectiveness (see PRECAUTIONS:
Information for Patients and PRECAUTIONS: Drug Interactions: Oral
Contraceptives).
Table 8
Acceptable Contraception Methods for Females of Reproductive
Potential
Pick from the following birth control options:
Option 1
Methods to
Use Alone
•
•
•
Intrauterine devices (IUDs)
Tubal sterilization
Patient’s partner had a vasectomy
OR
17
Option 2
Choose One
Hormone
Method AND
One Barrier
Method
Hormone Methods
choose 1
Estrogen and Progesterone
• Oral Contraceptive Pill
• Transdermal patch
• Vaginal ring
Progesterone-only
• Injection
• Implant
Barrier Methods
choose 1
•
•
AND •
•
•
Diaphragm with spermicide
Cervical cap with spermicide
Contraceptive sponge
Male condom
Female condom
OR
Option 3
Choose One
Barrier
Method from
each column
(must choose
two methods)
Barrier Methods
choose 1
• Diaphragm with spermicide
• Cervical cap with spermicide
• Contraceptive sponge
Barrier Methods
choose 1
• Male condom
AND • Female condom
Pregnancy Planning
For patients who are considering pregnancy, consider alternative immunosuppressants
with less potential for embryofetal toxicity. Risks and benefits of CellCept should be
discussed with the patient.
Gastrointestinal Disorders
Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately
3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with
CellCept 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal
bleeding (requiring hospitalization) were observed.
Gastrointestinal perforations have rarely been observed. Most patients receiving CellCept
were also receiving other drugs known to be associated with these complications. Patients
with active peptic ulcer disease were excluded from enrollment in studies with
mycophenolate mofetil. Because CellCept has been associated with an increased
incidence of digestive system adverse events, including infrequent cases of
gastrointestinal tract ulceration, hemorrhage, and perforation, CellCept should be
administered with caution in patients with active serious digestive system disease.
Patients with Renal Impairment
Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) who have
received single doses of CellCept showed higher plasma MPA and MPAG AUCs relative
to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data
18
are available on the safety of long-term exposure to these levels of MPAG. Doses of
CellCept greater than 1 g administered twice a day to renal transplant patients should be
avoided and they should be carefully observed (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
No data are available for cardiac or hepatic transplant patients with severe chronic renal
impairment. CellCept may be used for cardiac or hepatic transplant patients with severe
chronic renal impairment if the potential benefits outweigh the potential risks.
In patients with delayed renal graft function posttransplant, mean MPA AUC(0-12h) was
comparable, but MPAG AUC(0-12h) was 2-fold to 3-fold higher, compared to that seen
in posttransplant patients without delayed renal graft function. In the three controlled
studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with
delayed graft function. Although patients with delayed graft function have a higher
incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than
patients without delayed graft function, these events were not more frequent in patients
receiving CellCept than azathioprine or placebo. No dose adjustment is recommended for
these patients; however, they should be carefully observed (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Infections in Cardiac Transplant Patients
In cardiac transplant patients, the overall incidence of opportunistic infections was
approximately 10% higher in patients treated with CellCept than in those receiving
azathioprine therapy, but this difference was not associated with excess mortality due to
infection/sepsis among patients treated with CellCept (see ADVERSE REACTIONS).
There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in
cardiac transplant patients treated with CellCept compared to those treated with
azathioprine (see ADVERSE REACTIONS).
Concomitant Medications
It is recommended that CellCept not be administered concomitantly with azathioprine
because both have the potential to cause bone marrow suppression and such concomitant
administration has not been studied clinically.
In view of the significant reduction in the AUC of MPA by cholestyramine, caution
should be used in the concomitant administration of CellCept with drugs that interfere
with enterohepatic recirculation because of the potential to reduce the efficacy of
CellCept (see PRECAUTIONS: Drug Interactions).
Patients with HGPRT Deficiency
CellCept is an IMPDH (inosine monophosphate dehydrogenase) inhibitor; therefore it
should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine
phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller
syndrome.
19
Immunizations
During treatment with CellCept, the use of live attenuated vaccines should be avoided
and patients should be advised that vaccinations may be less effective (see
PRECAUTIONS: Drug Interactions: Live Vaccines).
Phenylketonurics
CellCept Oral Suspension contains aspartame, a source of phenylalanine (0.56 mg
phenylalanine/mL suspension). Therefore, care should be taken if CellCept Oral
Suspension is administered to patients with phenylketonuria.
Information for Patients
See Medication Guide
• Inform females of reproductive potential that use of CellCept during pregnancy is
associated with an increased risk of first trimester pregnancy loss and an increased
risk of congenital malformations, and advise them as to the appropriate steps to
manage these risks, including that they must use acceptable contraception (see
WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure
Prevention and Planning).
•
Discuss pregnancy testing, pregnancy prevention and planning with females of
reproductive potential. In the event of a positive pregnancy test, females should be
counseled with regard to whether the maternal benefits of mycophenolate treatment
may outweigh the risks to the fetus in certain situations.
•
Females of reproductive potential must use acceptable birth control during entire
CellCept therapy and for 6 weeks after stopping CellCept, unless the patient chooses
to avoid heterosexual intercourse completely (abstinence) (see PRECAUTIONS:
Pregnancy Exposure Prevention and Planning, Table 8).
•
For patients who are considering pregnancy, discuss appropriate alternative
immunosuppressants with less potential for embryofetal toxicity. Risks and benefits
of CellCept should be discussed with the patient.
•
Give patients complete dosage instructions and inform them about the increased risk
of lymphoproliferative disease and certain other malignancies.
•
Inform patients that they need repeated appropriate laboratory tests while they are
taking CellCept.
•
Advise patients that they should not breastfeed during CellCept therapy.
Laboratory Tests
Complete blood counts should be performed weekly during the first month, twice
monthly for the second and third months of treatment, then monthly through the first year
(see
WARNINGS,
ADVERSE
REACTIONS
and
DOSAGE
AND
ADMINISTRATION).
20
Drug Interactions
Drug interaction studies with mycophenolate mofetil have been conducted with
acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives,
sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug
interaction studies have not been conducted with other drugs that may be commonly
administered to renal, cardiac or hepatic transplant patients. CellCept has not been
administered concomitantly with azathioprine.
Acyclovir
Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy
volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG
and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because
MPAG plasma concentrations are increased in the presence of renal impairment, as are
acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its
prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the
concentrations of both drugs.
Antacids With Magnesium and Aluminum Hydroxides
Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when
administered to ten rheumatoid arthritis patients also taking Maalox TC (10 mL qid).
The Cmax and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when
mycophenolate mofetil was administered alone under fasting conditions. CellCept may
be administered to patients who are also taking antacids containing magnesium and
aluminum hydroxides; however, it is recommended that CellCept and the antacid not be
administered simultaneously.
®
Proton Pump Inhibitors (PPIs)
Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy
volunteers and multiple doses to transplant patients receiving CellCept has been reported
to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to
70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to
a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced
MPA exposure on organ rejection has not been established in transplant patients
receiving PPIs and CellCept. Because clinical relevance has not been established, PPIs
should be used with caution when coadministered to transplant patients being treated with
CellCept.
Cholestyramine
Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy
volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased
approximately 40%. This decrease is consistent with interruption of enterohepatic
recirculation which may be due to binding of recirculating MPAG with cholestyramine in
the intestine. Some degree of enterohepatic recirculation is also anticipated following
intravenous administration of CellCept. Therefore, CellCept is not recommended to be
given with cholestyramine or other agents that may interfere with enterohepatic
recirculation.
21
Cyclosporine
Cyclosporine (Sandimmune ) pharmacokinetics (at doses of 275 to 415 mg/day) were
unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10
stable renal transplant patients. The mean (±SD) AUC(0-12h) and Cmax of cyclosporine
after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng•h/mL and
753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng•h/mL and 700 (±246)
ng/mL, respectively, 1 week before administration of mycophenolate mofetil.
®
Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant
patients, mean MPA exposure (AUC0-12h) was approximately 30-50% greater when
mycophenolate mofetil is administered without cyclosporine compared with when
mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to
cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter
in the biliary tract, thereby preventing the excretion of MPAG into the bile that would
lead to enterohepatic recirculation of MPA. This information should be taken into
consideration when MMF is used without cyclosporine; changes in MPA exposure
should be expected when switching patients from cyclosporine A to one of the
immunosuppressants which do not interfere with MPA’s enterohepatic cycle (e.g.,
tacrolimus; belatacept).
Telmisartan
Concommitant administration of telmisartan and CellCept resulted in an approximately
30% decrease in mycophenolic acid (MPA) concentrations. Telmisartan changes MPA’s
elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor
gamma) expression, which in turn results in an enhanced UGT1A9 expression and
activity.
Ganciclovir
Following single-dose administration to 12 stable renal transplant patients, no
pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and
intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were
54.3 (±19.0) µg•h/mL and 11.5 (±1.8) µg/mL, respectively, after coadministration of the
two drugs, compared to 51.0 (±17.0) µg•h/mL and 10.6 (±2.0) µg/mL, respectively, after
administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA
(n=12) after coadministration were 80.9 (±21.6) µg•h/mL and 27.8 (±13.9) µg/mL,
respectively, compared to values of 80.3 (±16.4) µg•h/mL and 30.9 (±11.2) µg/mL,
respectively, after administration of mycophenolate mofetil alone. Because MPAG
plasma concentrations are increased in the presence of renal impairment, as are
ganciclovir concentrations, the two drugs will compete for tubular secretion and thus
further increases in concentrations of both drugs may occur. In patients with renal
impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are
coadministered, patients should be monitored carefully.
Oral Contraceptives
A study of coadministration of CellCept (1 g bid) and combined oral contraceptives
containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20
22
mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18
women with psoriasis over 3 consecutive menstrual cycles. Mean AUC(0-24h) was
similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel
AUC(0-24h) significantly decreased by about 15%. There was large inter-patient
variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol.
Mean serum levels of LH, FSH and progesterone were not significantly affected.
CellCept may not have any influence on the ovulation-suppressing action of the studied
oral contraceptives. It is recommended to coadminister CellCept with hormonal
contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and
implant) with caution and additional barrier contraceptive methods must be used (see
PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
Sevelamer
Concomitant administration of sevelamer and mycophenolate mofetil in adult and
pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26%
respectively. This data suggest that sevelamer and other calcium free phosphate binders
should not be administered simultaneously with CellCept. Alternatively, it is
recommended that sevelamer and other calcium free phosphate binders preferentially
could be given 2 hours after CellCept intake to minimize the impact on the absorption of
MPA.
Trimethoprim/sulfamethoxazole
Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy
male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole
800 mg administered bid, no effect on the bioavailability of MPA was observed. The
mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8)
µg•h/mL and 34.0 (±6.6) µg/mL, respectively, compared to 79.2 (±27.9) µg•h/mL and
34.2 (±10.7) µg/mL, respectively, after administration of mycophenolate mofetil alone.
Norfloxacin and Metronidazole
Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy
volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole,
the mean MPA AUC0-48h was significantly reduced by 33% compared to the
administration of mycophenolate mofetil alone (p<0.05). Therefore, CellCept is not
recommended to be given with the combination of norfloxacin and metronidazole. There
was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was
concomitantly administered with norfloxacin or metronidazole separately. The mean
(±SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin
or metronidazole separately was 48.3 (±24) µg·h/mL and 42.7 (±23) µg·h/mL,
respectively, compared with 56.2 (±24) µg·h/mL after administration of mycophenolate
mofetil alone.
Ciprofloxacin and Amoxicillin plus Clavulanic Acid
A total of 64 CellCept-treated renal transplant recipients received either oral
ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 or at least
14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (CellCept alone) were observed in 3 days following commencement
23
of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA
concentrations tended to diminish within 14 days of antibiotic therapy and ceased within
3 days after discontinuation of antibiotics. The postulated mechanism for this interaction
is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading
to a decrease in enterohepatic recirculation of MPA. The change in trough level may not
accurately represent changes in overall MPA exposure; therefore, clinical relevance of
these observations is unclear.
Rifampin
In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA
exposure (AUC0-12h) has been observed with concomitant administration of
mycophenolate mofetil and rifampin. Therefore, CellCept is not recommended to be
given with rifampin concomitantly unless the benefit outweighs the risk.
Other Interactions
The measured value for renal clearance of MPAG indicates removal occurs by renal
tubular secretion as well as glomerular filtration. Consistent with this, coadministration of
probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in
monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in
plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may
compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug
undergoing tubular secretion.
Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by
disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less
MPA available for absorption.
Live Vaccines
During treatment with CellCept, the use of live attenuated vaccines should be avoided
and patients should be advised that vaccinations may be less effective (see
PRECAUTIONS: Immunizations). Influenza vaccination may be of value. Prescribers
should refer to national guidelines for influenza vaccination.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses
up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the
recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the
recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for
differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats,
mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest
dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05
times the recommended clinical dose in cardiac transplant patients when corrected for
BSA. While these animal doses were lower than those given to patients, they were
maximal in those species and were considered adequate to evaluate the potential for
human risk (see WARNINGS).
The genotoxic potential of mycophenolate mofetil was determined in five assays.
Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay
24
and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in
the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese
hamster ovary cell chromosomal aberration assay.
Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to
20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal
transplant patients and 0.07 times the recommended clinical dose in cardiac transplant
patients when corrected for BSA. In a female fertility and reproduction study conducted
in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and
eyes) in the first generation offspring in the absence of maternal toxicity. This dose was
0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the
recommended clinical dose in cardiac transplant patients when corrected for BSA. No
effects on fertility or reproductive parameters were evident in the dams or in the
subsequent generation.
Pregnancy
Pregnancy Category D. See WARNINGS section.
Use of MMF during pregnancy is associated with an increased risk of first trimester
pregnancy loss and an increased risk of congenital malformations, especially external ear
and other facial abnormalities including cleft lip and palate, and anomalies of the distal
limbs, heart, esophagus, kidney, and nervous system. In animal studies, congenital
malformations and pregnancy loss occurred when pregnant rats and rabbits received
mycophenolic acid at dose multiples similar to and less than clinical doses. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking this drug, the
patient should be apprised of the potential hazard to the fetus.
Risks and benefits of CellCept should be discussed with the patient. When appropriate,
consider alternative immunosuppressants with less potential for embryofetal toxicity. In
certain situations, the patient and her healthcare practitioner may decide that the maternal
benefits outweigh the risks to the fetus. For those females using CellCept at any time
during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy,
the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy
Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the
patient to enroll in the pregnancy registry. The information provided to the registry will
help the healthcare community better understand the effects of mycophenolate in
pregnancy.
In the National Transplantation Pregnancy Registry (NTPR), there were data on 33
MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions
(45%) and 18 live-born infants. Four of these 18 infants had structural malformations
(22%). In postmarketing data (collected 1995-2007) on 77 females exposed to systemic
MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or
fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing
data are reported voluntarily, it is not always possible to reliably estimate the frequency
of particular adverse outcomes. These malformations are similar to findings in animal
reproductive toxicology studies. For comparison, the background rate for congenital
25
anomalies in the United States is about 3%, and NTPR data show a rate of 4-5% among
babies born to organ transplant patients using other immunosuppressive drugs.
In animal reproductive toxicology studies, there were increased rates of fetal resorptions
and malformations in the absence of maternal toxicity. Female rats and rabbits received
mycophenolate mofetil (MMF) doses equivalent to 0.02 to 0.9 times the recommended
human dose for renal and cardiac transplant patients, based on body surface area
conversions. In rat offspring, malformations included anophthalmia, agnathia, and
hydrocephaly. In rabbit offspring, malformations included ectopia cordis, ectopic
kidneys, diaphragmatic hernia, and umbilical hernia.
Nursing Mothers
Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be
excreted in milk. It is not known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk, and because of the potential for serious adverse
reactions in nursing infants from mycophenolate mofetil, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Based on pharmacokinetic and safety data in pediatric patients after renal transplantation,
the recommended dose of CellCept oral suspension is 600 mg/m2 bid (up to a maximum
of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES,
ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.
Safety and effectiveness in pediatric patients receiving allogeneic cardiac or hepatic
transplants have not been established.
Geriatric Use
Clinical studies of CellCept did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and
younger patients. In general dose selection for an elderly patient should be cautious,
reflecting the greater frequency of decreased hepatic, renal or cardiac function and of
concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse
reactions compared with younger individuals (see ADVERSE REACTIONS).
ADVERSE REACTIONS
The principal adverse reactions associated with the administration of CellCept include
diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of
certain types of infections eg, opportunistic infection (see WARNINGS: Serious
Infections and WARNINGS: New or Reactivated Viral Infections). The adverse event
profile associated with the administration of CellCept Intravenous has been shown to be
similar to that observed after administration of oral dosage forms of CellCept.
CellCept Oral
The incidence of adverse events for CellCept was determined in randomized,
comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo26
controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial)
transplant patients.
Geriatrics
Elderly patients (≥65 years), particularly those who are receiving CellCept as part of a
combination immunosuppressive regimen, may be at increased risk of certain infections
(including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal
hemorrhage and pulmonary edema, compared to younger individuals (see
PRECAUTIONS).
Safety data are summarized below for all active-controlled trials in renal (2 trials),
cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53% of the renal
patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated
for more than 1 year. Adverse events reported in ≥20% of patients in the CellCept
treatment groups are presented below.
Table 9
Adverse Events in Controlled Studies in Prevention of
Renal, Cardiac or Hepatic Allograft Rejection (Reported in
≥20% of Patients in the CellCept Group)
Renal Studies
Cardiac Study
Hepatic Study
Azathioprine
1 to
Azathioprine
Azathioprine
CellCept CellCept
CellCept
CellCept
2 mg/kg/day or
1.5 to 3
1 to
2 g/day 3 g/day
3 g/day
3 g/day
100 to 150
mg/kg/day
2 mg/kg/day
mg/day
(n=336) (n=330)
(n=326)
(n=289)
(n=289)
(n=277)
(n=287)
%
%
%
%
%
%
%
Body as a Whole
Pain
Abdominal pain
Fever
Headache
Infection
Sepsis
Asthenia
Chest pain
Back pain
Ascites
Hematologic and
Lymphatic
Anemia
Leukopenia
Thrombocytopenia
Hypochromic
anemia
Leukocytosis
Urogenital
Urinary tract
infection
Kidney function
abnormal
33.0
24.7
21.4
21.1
18.2
–
–
–
–
–
31.2
27.6
23.3
16.1
20.9
–
–
–
–
–
32.2
23.0
23.3
21.2
19.9
–
–
–
–
–
75.8
33.9
47.4
54.3
25.6
–
43.3
26.3
34.6
–
74.7
33.2
46.4
51.9
19.4
–
36.3
26.0
28.4
–
74.0
62.5
52.3
53.8
27.1
27.4
35.4
–
46.6
24.2
77.7
51.2
56.1
49.1
25.1
26.5
33.8
–
47.4
22.6
25.6
23.2
–
25.8
34.5
–
23.6
24.8
–
42.9
30.4
23.5
43.9
39.1
27.0
43.0
45.8
38.3
53.0
39.0
42.2
–
–
–
24.6
23.5
–
–
–
–
–
40.5
35.6
22.4
21.3
37.2
37.0
33.7
–
–
–
–
–
–
–
21.8
26.3
25.6
28.9
27
Renal Studies
Cardiac Study
Hepatic Study
Azathioprine
1 to
Azathioprine
Azathioprine
CellCept CellCept
CellCept
CellCept
2 mg/kg/day or
1.5 to 3
1 to
2 g/day 3 g/day
3 g/day
3 g/day
100 to 150
mg/kg/day
2 mg/kg/day
mg/day
(n=336) (n=330)
(n=326)
(n=289)
(n=289)
(n=277)
(n=287)
%
%
%
%
%
%
%
Cardiovascular
Hypertension
Hypotension
Cardiovascular
disorder
Tachycardia
Metabolic and
Nutritional
Peripheral edema
Hypercholesteremia
Edema
Hypokalemia
Hyperkalemia
Hyperglycemia
Creatinine
increased
BUN increased
Lactic
dehydrogenase
increased
Hypomagnesemia
Hypocalcemia
Digestive
Diarrhea
Constipation
Nausea
Dyspepsia
Vomiting
Anorexia
Liver function tests
abnormal
Respiratory
Infection
Dyspnea
Cough increased
Lung disorder
Sinusitis
Pleural effusion
Skin and
Appendages
Rash
32.4
–
28.2
–
32.2
–
77.5
32.5
72.3
36.0
62.1
–
59.6
–
–
–
–
25.6
24.2
–
–
–
–
–
20.1
18.0
22.0
15.7
28.6
27.0
28.2
64.0
53.3
48.4
47.7
–
–
–
41.2
38.4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
26.6
31.8
–
46.7
25.6
25.6
–
52.6
28.2
37.2
22.0
43.7
28.2
41.1
23.7
48.8
–
–
–
39.4
36.0
–
–
–
–
–
34.6
32.5
–
–
–
–
–
23.2
17.0
–
–
–
–
–
–
–
–
–
–
–
–
39.0
30.0
37.6
30.0
31.0
22.9
19.9
–
–
–
36.1
18.5
23.6
–
–
–
20.9
22.4
24.5
–
–
–
45.3
41.2
54.0
–
33.9
–
34.3
37.7
54.3
–
28.4
–
51.3
37.9
54.5
22.4
32.9
25.3
49.8
38.3
51.2
20.9
33.4
17.1
–
–
–
–
–
24.9
19.2
22.0
–
–
–
–
–
23.9
–
–
–
–
–
19.6
–
–
–
–
–
37.0
36.7
31.1
30.1
26.0
–
35.3
36.3
25.6
29.1
19.0
–
–
31.0
–
22.0
–
34.3
–
30.3
–
18.8
–
35.9
–
–
–
22.1
18.0
–
–
28
Renal Studies
Cardiac Study
Hepatic Study
Azathioprine
1 to
Azathioprine
Azathioprine
CellCept CellCept
CellCept
CellCept
2 mg/kg/day or
1.5 to 3
1 to
2 g/day 3 g/day
3 g/day
3 g/day
100 to 150
mg/kg/day
2 mg/kg/day
mg/day
(n=336) (n=330)
(n=326)
(n=289)
(n=289)
(n=277)
(n=287)
%
%
%
%
%
%
%
Nervous System
Tremor
Insomnia
Dizziness
Anxiety
Paresthesia
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
24.2
40.8
28.7
28.4
20.8
23.9
37.7
27.7
23.9
18.0
33.9
52.3
–
–
–
35.5
47.0
–
–
–
The placebo-controlled renal transplant study generally showed fewer adverse events
occurring in ≥20% of patients. In addition, those that occurred were not only qualitatively
similar to the azathioprine-controlled renal transplant studies, but also occurred at lower
rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory
infection.
The above data demonstrate that in three controlled trials for prevention of renal
rejection, patients receiving 2 g/day of CellCept had an overall better safety profile than
did patients receiving 3 g/day of CellCept.
The above data demonstrate that the types of adverse events observed in multicenter
controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar
except for those that are unique to the specific organ involved.
Sepsis, which was generally CMV viremia, was slightly more common in renal transplant
patients treated with CellCept compared to patients treated with azathioprine. The
incidence of sepsis was comparable in CellCept and in azathioprine-treated patients in
cardiac and hepatic studies.
In the digestive system, diarrhea was increased in renal and cardiac transplant patients
receiving CellCept compared to patients receiving azathioprine, but was comparable in
hepatic transplant patients treated with CellCept or azathioprine.
Patients receiving CellCept alone or as part of an immunosuppressive regimen are at
increased risk of developing lymphomas and other malignancies, particularly of the skin
(see WARNINGS: Lymphoma and Malignancy). The incidence of malignancies
among the 1483 patients treated in controlled trials for the prevention of renal allograft
rejection who were followed for ≥1 year was similar to the incidence reported in the
literature for renal allograft recipients.
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving
CellCept (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical
trials of renal, cardiac, and hepatic transplant patients followed for at least 1 year (see
WARNINGS: Lymphoma and Malignancy). Non-melanoma skin carcinomas occurred
in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients.
29
Three-year safety data in renal and cardiac transplant patients did not reveal any
unexpected changes in incidence of malignancy compared to the 1-year data.
In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148
patients) have been observed.
Severe neutropenia (ANC <0.5 x 103/µL) developed in up to 2.0% of renal transplant
patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant
patients receiving CellCept 3 g daily (see WARNINGS: Neutropenia,
PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION).
All transplant patients are at increased risk of opportunistic infections. The risk increases
with total immunosuppressive load (see WARNINGS: Serious Infections and
WARNINGS: New or Reactivated Viral Infections). Table 10 shows the incidence of
opportunistic infections that occurred in the renal, cardiac, and hepatic transplant
populations in the azathioprine-controlled prevention trials:
Table 10
Herpes simplex
CMV
– Viremia/syndrome
– Tissue invasive
disease
Herpes zoster
– Cutaneous disease
Candida
– Mucocutaneous
Viral and Fungal Infections in Controlled Studies in
Prevention of Renal, Cardiac or Hepatic Transplant
Rejection
Renal Studies
Cardiac Study
Hepatic Study
Azathioprine
1 to
Azathioprine
Azathioprine
CellCept CellCept
CellCept
CellCept
2 mg/kg/day
1.5 to
1 to
2 g/day 3 g/day
3 g/day
3 g/day
or 100 to 150
3 mg/kg/day
2 mg/kg/day
mg/day
(n=336) (n=330)
(n=326)
(n=289)
(n=289)
(n=277)
(n=287)
%
%
%
%
%
%
%
16.7
20.0
19.0
20.8
14.5
10.1
5.9
13.4
12.4
13.8
12.1
10.0
14.1
12.2
8.3
11.5
6.1
11.4
8.7
5.8
8.0
6.0
6.0
17.0
15.5
7.6
7.3
17.3
16.4
5.8
5.5
18.1
15.3
10.7
10.0
18.7
18.0
5.9
5.5
17.6
17.3
4.3
4.3
22.4
18.4
4.9
4.9
24.4
17.4
The following other opportunistic infections occurred with an incidence of less than 4%
in CellCept patients in the above azathioprine-controlled studies: Herpes zoster, visceral
disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive
disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii.
In the placebo-controlled renal transplant study, the same pattern of opportunistic
infection was observed compared to the azathioprine-controlled renal studies, with a
notably lower incidence of the following: Herpes simplex and CMV tissue-invasive
disease.
In patients receiving CellCept (2 g or 3 g) in controlled studies for prevention of renal,
cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal
and cardiac patients and in 5% of hepatic patients (see WARNINGS: Serious
30
Infections). In cardiac transplant patients, the overall incidence of opportunistic infections
was approximately 10% higher in patients treated with CellCept than in those receiving
azathioprine, but this difference was not associated with excess mortality due to
infection/sepsis among patients treated with CellCept.
The following adverse events were reported with 3% to <20% incidence in renal, cardiac,
and hepatic transplant patients treated with CellCept, in combination with cyclosporine
and corticosteroids.
31
Table 11
Adverse Events Reported in 3% to <20% of Patients Treated
With CellCept in Combination With Cyclosporine and
Corticosteroids
Body System
Body as a
Whole
abdomen enlarged, abscess, accidental injury, cellulitis, chills
occurring with fever, cyst, face edema, flu syndrome, hemorrhage,
hernia, lab test abnormal, malaise, neck pain, pelvic pain, peritonitis
Hematologic
and Lymphatic
coagulation disorder, ecchymosis, pancytopenia, petechia,
polycythemia, prothrombin time increased, thromboplastin time
increased
Urogenital
acute kidney failure, albuminuria, dysuria, hydronephrosis,
hematuria, impotence, kidney failure, kidney tubular necrosis,
nocturia, oliguria, pain, prostatic disorder, pyelonephritis, scrotal
edema, urine abnormality, urinary frequency, urinary incontinence,
urinary retention, urinary tract disorder
Cardiovascular
angina pectoris, arrhythmia, arterial thrombosis, atrial fibrillation,
atrial flutter, bradycardia, cardiovascular disorder, congestive heart
failure, extrasystole, heart arrest, heart failure, hypotension, pallor,
palpitation, pericardial effusion, peripheral vascular disorder, postural
hypotension, pulmonary hypertension, supraventricular tachycardia,
supraventricular extrasystoles, syncope, tachycardia, thrombosis,
vasodilatation, vasospasm, ventricular extrasystole, ventricular
tachycardia, venous pressure increased
Metabolic and
Nutritional
abnormal healing, acidosis, alkaline phosphatase increased, alkalosis,
bilirubinemia, creatinine increased, dehydration, gamma glutamyl
transpeptidase increased, generalized edema, gout, hypercalcemia,
hypercholesteremia, hyperlipemia, hyperphosphatemia,
hyperuricemia, hypervolemia, hypocalcemia, hypochloremia,
hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia,
hypovolemia, hypoxia, lactic dehydrogenase increased, respiratory
acidosis, SGOT increased, SGPT increased, thirst, weight gain,
weight loss
Digestive
anorexia, cholangitis, cholestatic jaundice, dysphagia, esophagitis,
flatulence, gastritis, gastroenteritis, gastrointestinal disorder,
gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis,
gum hyperplasia, hepatitis, ileus, infection, jaundice, liver damage,
liver function tests abnormal, melena, mouth ulceration, nausea and
vomiting, oral moniliasis, rectal disorder, stomach ulcer, stomatitis
32
Body System
Respiratory
apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup,
hyperventilation, lung edema, lung disorder, neoplasm, pain,
pharyngitis, pleural effusion, pneumonia, pneumothorax, respiratory
disorder, respiratory moniliasis, rhinitis, sinusitis, sputum increased,
voice alteration
Skin and
Appendages
acne, alopecia, fungal dermatitis, hemorrhage, hirsutism, pruritus,
rash, skin benign neoplasm, skin carcinoma, skin disorder, skin
hypertrophy, skin ulcer, sweating, vesiculobullous rash
Nervous
agitation, anxiety, confusion, convulsion, delirium, depression, dry
mouth, emotional lability, hallucinations, hypertonia, hypesthesia,
nervousness, neuropathy, paresthesia, psychosis, somnolence,
thinking abnormal, vertigo
Endocrine
Cushing’s syndrome, diabetes mellitus, hypothyroidism, parathyroid
disorder
Musculoskeletal
arthralgia, joint disorder, leg cramps, myalgia, myasthenia,
osteoporosis
Special Senses
abnormal vision, amblyopia, cataract (not specified), conjunctivitis,
deafness, ear disorder, ear pain, eye hemorrhage, tinnitus, lacrimation
disorder
Pediatrics
The type and frequency of adverse events in a clinical study in 100 pediatric patients 3
months to 18 years of age dosed with CellCept oral suspension 600 mg/m2 bid (up to 1 g
bid) were generally similar to those observed in adult patients dosed with CellCept
capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain,
sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension,
leukopenia, and anemia, which were observed in a higher proportion in pediatric patients.
CellCept Intravenous
The adverse event profile of CellCept Intravenous was determined from a single, doubleblind, controlled comparative study of the safety of 2 g/day of intravenous and oral
CellCept in renal transplant patients in the immediate posttransplant period (administered
for the first 5 days). The potential venous irritation of CellCept Intravenous was
evaluated by comparing the adverse events attributable to peripheral venous infusion of
CellCept Intravenous with those observed in the intravenous placebo group; patients in
this group received active medication by the oral route.
Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis,
both observed at 4% in patients treated with CellCept Intravenous.
33
In the active controlled study in hepatic transplant patients, 2 g/day of CellCept
Intravenous were administered in the immediate posttransplant period (up to 14 days).
The safety profile of intravenous CellCept was similar to that of intravenous azathioprine.
Postmarketing Experience
Congenital Disorders: Embryofetal Toxicity: Congenital malformations, including ear,
facial, cardiac and nervous system malformations and an increased incidence of first
trimester pregnancy loss have been reported following exposure to mycophenolate
mofetil during pregnancy (see PRECAUTIONS: Pregnancy).
Digestive: Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of
intestinal villous atrophy.
Hematologic and Lymphatic: Cases of pure red cell aplasia (PRCA) and
hypogammaglobulinemia have been reported in patients treated with CellCept in
combination with other immunosuppressive agents.
Infections (see WARNINGS: Serious Infections, New or Reactivated Viral
Infections):
•
Serious life-threatening infections such as meningitis and infectious endocarditis
have been reported occasionally.
•
There is evidence of a higher frequency of certain types of serious infections such
as tuberculosis and atypical mycobacterial infection.
•
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal,
have been reported in patients treated with CellCept. The reported cases generally
had risk factors for PML, including treatment with immunosuppressant therapies
and impairment of immune function.
•
Polyomavirus associated neuropathy (PVAN), especially due to BK virus
infection, has been observed in patients receiving immunosuppressants, including
CellCept. This infection is associated with serious outcomes, including
deteriorating renal function and renal graft loss.
•
Viral reactivation has been reported in patients infected with HBV or HCV.
Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis, have been
reported rarely and should be considered in the differential diagnosis of pulmonary
symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving
CellCept.
OVERDOSAGE
The experience with overdose of CellCept in humans is very limited. The events received
from reports of overdose fall within the known safety profile of the drug. The highest
dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited
experience with cardiac and hepatic transplant patients in clinical trials, the highest doses
used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher
rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea,
34
vomiting, and/or diarrhea), and occasional hematologic abnormalities, principally
neutropenia, leading to a need to reduce or discontinue dosing.
In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg
or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of
mycophenolate mofetil tested in these species. These doses represent 11 times the
recommended clinical dose in renal transplant patients and approximately 7 times the
recommended clinical dose in cardiac transplant patients when corrected for BSA. In
adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate
mofetil. The dose represents approximately 3 times the recommended clinical dose in
cardiac transplant patients when corrected for BSA.
MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG
plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By
increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as
cholestyramine (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DOSAGE AND ADMINISTRATION
Renal Transplantation
Adults
A dose of 1 g administered orally or intravenously (over NO LESS THAN 2 HOURS)
twice a day (daily dose of 2 g) is recommended for use in renal transplant patients.
Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical
trials and was shown to be safe and effective, no efficacy advantage could be established
for renal transplant patients. Patients receiving 2 g/day of CellCept demonstrated an
overall better safety profile than did patients receiving 3 g/day of CellCept.
Pediatrics (3 months to 18 years of age)
The recommended dose of CellCept oral suspension is 600 mg/m2 administered twice
daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body
surface area of 1.25 m2 to 1.5 m2 may be dosed with CellCept capsules at a dose of 750
mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be
dosed with CellCept capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
Cardiac Transplantation
Adults
A dose of 1.5 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5
g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
Hepatic Transplantation
Adults
A dose of 1 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g
bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.
35
CellCept Capsules, Tablets, and Oral Suspension
The initial oral dose of CellCept should be given as soon as possible following renal,
cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown
to decrease MPA Cmax by 40%. Therefore, it is recommended that CellCept be
administered on an empty stomach. However, in stable renal transplant patients, CellCept
may be administered with food if necessary.
Patients should be instructed to take a missed dose as soon as they remember, except if it
is near the next scheduled dose, and then continue to take CellCept at the usual times.
Note:
If required, CellCept Oral Suspension can be administered via a nasogastric tube with a
minimum size of 8 French (minimum 1.7 mm interior diameter).
Patients With Hepatic Impairment
No dose adjustments are recommended for renal patients with severe hepatic
parenchymal disease. However, it is not known whether dose adjustments are needed for
hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
No data are available for cardiac transplant patients with severe hepatic parenchymal
disease.
Geriatrics
The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac
transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered
orally in hepatic transplant patients is appropriate for elderly patients (see
PRECAUTIONS: Geriatric Use).
Preparation of Oral Suspension
It is recommended that CellCept Oral Suspension be constituted by the pharmacist prior
to dispensing to the patient.
CellCept Oral Suspension should not be mixed with any other medication.
Mycophenolate mofetil has demonstrated teratogenic effects in humans. There are no
adequate and well-controlled studies in pregnant women (see WARNINGS,
PRECAUTIONS, ADVERSE REACTIONS, and HANDLING AND DISPOSAL).
Care should be taken to avoid inhalation or direct contact with skin or mucous
membranes of the dry powder or the constituted suspension. If such contact occurs, wash
thoroughly with soap and water; rinse eyes with water.
1. Tap the closed bottle several times to loosen the powder.
2. Measure 94 mL of water in a graduated cylinder.
3. Add approximately half the total amount of water for constitution to the bottle and
shake the closed bottle well for about 1 minute.
4. Add the remainder of water and shake the closed bottle well for about 1 minute.
5. Remove the child-resistant cap and push bottle adapter into neck of bottle.
36
6. Close bottle with child-resistant cap tightly. This will assure the proper seating of the
bottle adapter in the bottle and child-resistant status of the cap.
Dispense with patient instruction sheet and oral dispensers. It is recommended to write
the date of expiration of the constituted suspension on the bottle label. (The shelf-life of
the constituted suspension is 60 days.)
After constitution the oral suspension contains 200 mg/mL mycophenolate mofetil. Store
constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze. Discard
any unused portion 60 days after constitution.
CellCept Intravenous
Adults
CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral
suspension recommended for patients unable to take oral CellCept. CellCept Intravenous
should be administered within 24 hours following transplantation. CellCept Intravenous
can be administered for up to 14 days; patients should be switched to oral CellCept as
soon as they can tolerate oral medication.
CellCept Intravenous must be reconstituted and diluted to a concentration of 6 mg/mL
using 5% Dextrose Injection USP. CellCept Intravenous is incompatible with other
intravenous infusion solutions. Following reconstitution, CellCept Intravenous must be
administered by slow intravenous infusion over a period of NO LESS THAN 2 HOURS
by either peripheral or central vein.
CAUTION: CELLCEPT INTRAVENOUS SOLUTION MUST NOT BE
ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION (see
WARNINGS).
Preparation of Infusion Solution (6 mg/mL)
Caution should be exercised in the handling and preparation of solutions of CellCept
Intravenous. Avoid direct contact of the prepared solution of CellCept Intravenous with
skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water;
rinse eyes with plain water (see WARNINGS, PRECAUTIONS, ADVERSE
REACTIONS, and HANDLING AND DISPOSAL).
CellCept Intravenous does not contain an antibacterial preservative; therefore,
reconstitution and dilution of the product must be performed under aseptic conditions.
Additionally, this product is sealed under vacuum and should retain a vacuum throughout
its shelf life. If a lack of vacuum in the vial is noted while adding diluent, the vial should
not be used.
CellCept Intravenous infusion solution must be prepared in two steps: the first step is a
reconstitution step with 5% Dextrose Injection USP, and the second step is a dilution step
with 5% Dextrose Injection USP. A detailed description of the preparation is given
below:
37
Step 1
a) Two (2) vials of CellCept Intravenous are used for preparing each 1 g dose, whereas
three (3) vials are needed for each 1.5 g dose. Reconstitute the contents of each vial
by injecting 14 mL of 5% Dextrose Injection USP.
b) Gently shake the vial to dissolve the drug.
c) Inspect the resulting slightly yellow solution for particulate matter and discoloration
prior to further dilution. Discard the vials if particulate matter or discoloration is
observed.
Step 2
a) To prepare a 1 g dose, further dilute the contents of the two reconstituted vials
(approx. 2 x 15 mL) into 140 mL of 5% Dextrose Injection USP. To prepare a 1.5 g
dose, further dilute the contents of the three reconstituted vials (approx. 3 x 15 mL)
into 210 mL of 5% Dextrose Injection USP. The final concentration of both solutions
is 6 mg mycophenolate mofetil per mL.
b) Inspect the infusion solution for particulate matter or discoloration. Discard the
infusion solution if particulate matter or discoloration is observed.
If the infusion solution is not prepared immediately prior to administration, the
commencement of administration of the infusion solution should be within 4 hours from
reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions
permitted to 15° to 30°C (59° to 86°F).
CellCept Intravenous should not be mixed or administered concurrently via the same
infusion catheter with other intravenous drugs or infusion admixtures.
Dosage Adjustments
In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73
m2) outside the immediate posttransplant period, doses of CellCept greater than 1 g
administered twice a day should be avoided. These patients should also be carefully
observed. No dose adjustments are needed in renal transplant patients experiencing
delayed graft function postoperatively (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).
No data are available for cardiac or hepatic transplant patients with severe chronic renal
impairment. CellCept may be used for cardiac or hepatic transplant patients with severe
chronic renal impairment if the potential benefits outweigh the potential risks.
If neutropenia develops (ANC <1.3 x 103/µL), dosing with CellCept should be
interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient
managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS,
and PRECAUTIONS: Laboratory Tests).
38
HANDLING AND DISPOSAL
Mycophenolate mofetil has demonstrated teratogenic effects in humans (see Pregnancy
and WARNINGS: Embryofetal Toxicity). CellCept tablets should not be crushed and
CellCept capsules should not be opened or crushed. Avoid inhalation or direct contact
with skin or mucous membranes of the powder contained in CellCept capsules and
CellCept Oral Suspension (before or after constitution). If such contact occurs, wash
thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe
up using paper towels wetted with water to remove spilled powder or suspension. Caution
should be exercised in the handling and preparation of solutions of CellCept Intravenous.
Avoid direct contact of the prepared solution of CellCept Intravenous with skin or
mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse
eyes with plain water.
HOW SUPPLIED
CellCept (mycophenolate mofetil capsules) 250 mg
Blue-brown, two-piece hard gelatin capsules, printed in black with “CellCept 250” on the
blue cap and “Roche” on the brown body. Supplied in the following presentations:
NDC Number
Size
NDC 0004-0259-01
NDC 0004-0259-05
NDC 0004-0259-43
Bottle of 100
Package containing 12 bottles of 120
Bottle of 500
Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
CellCept (mycophenolate mofetil tablets) 500 mg
Lavender-colored, caplet-shaped, film-coated tablets printed in black with “CellCept
500” on one side and “Roche” on the other. Supplied in the following presentations:
NDC Number
Size
NDC 0004-0260-01
NDC 0004-0260-43
Bottle of 100
Bottle of 500
Storage and Dispensing Information
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in
light-resistant containers, such as the manufacturer’s original containers.
CellCept Oral Suspension (mycophenolate mofetil for oral suspension)
Supplied as a white to off-white powder blend for constitution to a white to off-white
mixed-fruit flavor suspension. Supplied in the following presentation:
NDC Number
Size
NDC 0004-0261-29
225 mL bottle with bottle adapter and 2 oral dispensers
39
Storage
Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to
86°F) for up to 60 days. Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable.
Do not freeze.
CellCept Intravenous (mycophenolate mofetil hydrochloride for injection)
Supplied in a 20 mL, sterile vial containing the equivalent of 500 mg mycophenolate
mofetil as the hydrochloride salt in cartons of 4 vials:
NDC Number
NDC 0004-0298-09
Storage
Store powder and reconstituted/infusion solutions at 25°C (77°F); excursions permitted to
15° to 30°C (59° to 86°F).
PI Revised: July 2015
40
MEDICATION GUIDE
CellCept [SEL-sept]
(mycophenolate mofetil capsules)
(mycophenolate mofetil tablets)
®
CellCept Oral Suspension
(mycophenolate mofetil for oral suspension)
®
CellCept Intravenous
(mycophenolate mofetil hydrochloride for injection)
®
Read the Medication Guide that comes with CellCept before you start taking
it and each time you refill your prescription. There may be new information.
This Medication Guide does not take the place of talking with your doctor
about your medical condition or your treatment.
What is the most important information I should know about
CellCept?
CellCept can cause serious side effects:
•
Increased risk of loss of a pregnancy (miscarriage) and higher
risk of birth defects. Females who take CellCept during pregnancy
have a higher risk of miscarriage during the first 3 months (first
trimester), and a higher risk that their baby will be born with birth
defects.
If you are a female who can become pregnant
•
•
•
your doctor must talk with you about acceptable birth control
methods (contraceptive counseling) to use while taking CellCept.
you should have one pregnancy test immediately before starting
CellCept and another pregnancy test 8 to 10 days later. Pregnancy
tests should be repeated during routine follow-up visits with your
doctor. Talk to your doctor about the results of all of your
pregnancy tests.
you must use acceptable birth control during your entire CellCept
therapy and for 6 weeks after stopping CellCept, unless at any time
you choose to avoid sexual intercourse (abstinence) with a man
completely.
CellCept decreases blood levels of the hormones in birth control
pills that you take by mouth. Birth control pills may not work as
well while you take CellCept, and you could become pregnant. If
you take birth control pills while using CellCept you must also use
another form of birth control. Talk to your doctor about other birth
control methods that you can use while taking CellCept.
41
If you plan to become pregnant, talk with your doctor. Your doctor
will decide if other medicines to prevent rejection may be right for
you.
If you become pregnant while taking CellCept, do not stop
taking CellCept. Call your doctor right away. In certain
situations, you and your doctor may decide that taking CellCept is
more important to your health than the possible risks to your
unborn baby.
•
You and your doctor should report your pregnancy to
§
Mycophenolate Pregnancy Registry (1-800-617-8191)
The purpose of this registry is to gather information about the
health of you and your baby.
•
Increased risk of getting serious infections. CellCept weakens the
body’s immune system and affects your ability to fight infections.
Serious infections can happen with CellCept and can lead to death.
These serious infections can include:
•
Viral infections. Certain viruses can live in your body and
cause active infections when your immune system is weak. Viral
infections that can happen with CellCept include:
• Shingles, other herpes infections, and cytomegalovirus
(CMV). CMV can cause serious tissue and blood infections.
• BK virus. BK virus can affect how your kidney works and
cause your transplanted kidney to fail.
• Hepatitis B and C viruses. Hepatitis viruses can affect
how your liver works. Talk to your doctor about how
hepatitis viruses may affect you.
•
A brain infection called Progressive Multifocal
Leukoencephalopathy (PML). In some patients, CellCept may
cause an infection of the brain that may cause death. You are at
risk for this brain infection because you have a weakened
immune system. You should tell your doctor right away if you
have any of the following symptoms:
• Weakness on one side of the body
• You do not care about things that you usually care about
(apathy)
• You are confused or have problems thinking
• You can not control your muscles
42
•
Fungal infections. Yeasts and other types of fungal infections
can happen with CellCept and can cause serious tissue and
blood infections (see “What are the possible side effects of
CellCept?”)
Call your doctor right away if you have any of the following signs and
symptoms of infection:
•
•
•
•
•
•
•
•
•
Temperature of 100.5°F or greater
Cold symptoms, such as a runny nose or sore throat
Flu symptoms, such as an upset stomach, stomach pain,
vomiting or diarrhea
Earache or headache
Pain during urination
White patches in the mouth or throat
Unexpected bruising or bleeding
Cuts, scrapes or incisions that are red, warm and oozing pus
Increased risk of getting certain cancers. People who take
CellCept have a higher risk of getting lymphoma, and other cancers,
especially skin cancer. Tell your doctor if you have:
•
•
•
•
•
unexplained fever, prolonged tiredness, weight loss or lymph
node swelling
a brown or black skin lesion with uneven borders, or one part of
the lesion does not look like the other
a change in the size and color of a mole
a new skin lesion or bump
any other changes to your health
See the section “What are the possible side effects of CellCept?” for
information about other serious side effects.
What is CellCept?
CellCept is a prescription medicine to prevent rejection (antirejection
medicine) in people who have received a kidney, heart or liver transplant.
Rejection is when the body’s immune system perceives the new organ as a
“foreign” threat and attacks it.
CellCept is used with other medicines called cyclosporine (Sandimmune ,
Gengraf , Neoral ) and corticosteroids.
®
®
®
CellCept has been used safely and works in children who received a kidney
transplant as it does in adults. It is not known if CellCept is safe and works in
children who receive a heart or liver transplant.
43
Who should not take CellCept?
Do not take CellCept if you are allergic to mycophenolate mofetil or
any of the ingredients in CellCept. See the end of this Medication Guide
for a complete list of ingredients in CellCept.
What should I tell my doctor before taking CellCept?
Tell your doctor about all of your medical conditions, if you:
•
•
•
•
•
•
have any digestive problems, such as ulcers.
have Phenylketonuria (PKU). CellCept oral suspension contains
aspartame (a source of phenylalanine).
have Lesch-Nyhan or Kelley-Seegmiller syndrome or another
rare inherited deficiency hypoxanthine-guanine
phosphoribosyl-transferase (HGPRT). You should not take
CellCept if you have one of these disorders.
plan to receive any vaccines. People taking CellCept should not
take live vaccines. Some vaccines may not work as well during
treatment with CellCept.
are pregnant or are planning to become pregnant. See “What is
the most important information I should know about CellCept?”
are breastfeeding or plan to breastfeed. It is not known if CellCept
passes into breast milk. You and your doctor will decide if you will take
CellCept or breastfeed.
Tell your healthcare provider about all of the medicines you are
taking including prescription and nonprescription medicines,
vitamins and herbal supplements. Some medicines may affect the way
CellCept works, and CellCept may affect how some medicines work.
Especially tell your doctor if you take:
•
•
•
birth control pills (oral contraceptives). See “What is the most
important information I should know about CellCept?”
sevelamer (Renagel , Renvela™). These products should be taken 2
hours after taking CellCept
acyclovir (Zovirax ), valacyclovir (Valtrex ), ganciclovir (CYTOVENE -IV,
Vitrasert ), valganciclovir (VALCYTE )
rifampin (Rifater , Rifamate , Rimactane , Rifadin )
antacids that contain magnesium and aluminum (CellCept and the
antacid should not be taken at the same time)
proton pump inhibitors (PPIs) (Prevacid , Protonix )
sulfamethoxazole/trimethoprim (BACTRIM™, BACTRIM DS™)
norfloxacin (Noroxin ) and metronidazole (Flagyl , Flagyl ER, Flagyl IV,
Metro IV, Helidac , Pylera™)
ciprofloxacin (Cipro , Cipro XR, Ciloxan , Proquin XR) and amoxicillin
plus clavulanic acid (Augmentin , Augmentin XR™)
azathioprine (Azasan , Imuran )
®
®
®
®
•
•
•
•
•
®
®
®
®
®
®
®
®
®
®
®
®
®
•
®
®
®
®
®
•
®
®
44
•
cholestyramine (Questran Light , Questran , Locholest Light, Locholest,
Prevalite )
®
®
®
Know the medicines you take. Keep a list of them to show to your doctor or
nurse and pharmacist when you get a new medicine. Do not take any new
medicine without talking with your doctor.
How should I take CellCept?
•
Take CellCept exactly as prescribed.
•
Do not stop taking CellCept or change the dose unless your doctor tells
you to.
•
If you miss a dose of CellCept, or are not sure when you took your last
dose, take the regular amount of CellCept prescribed as soon as you
remember. If it is time for your next dose, skip the missed dose and
take your next dose at your normal scheduled time. Do not take 2
doses at the same time. Call your doctor if you are not sure what to
do.
•
Take CellCept capsules, tablets and oral suspension on an empty
stomach, either 1 hour before or 2 hours after a meal, unless your
healthcare provider tells you otherwise. With the approval of your
healthcare provider, in stable kidney transplant patients, CellCept can
be taken with food if necessary.
•
Most people take CellCept by mouth either as blue and brown capsules
or lavender tablets. Some people may get CellCept soon after their
transplant surgery as an infusion into a vein.
•
Do not crush CellCept tablets. Do not open or crush CellCept capsules.
•
If you are not able to swallow CellCept tablets or capsules, your doctor
may prescribe CellCept Oral Suspension. This is a liquid form of
CellCept. Your pharmacist will mix the medicine before giving it to you.
•
Do not mix CellCept Oral Suspension with any other medicine.
•
If you take too much CellCept, call your doctor or the poison control
center right away.
What should I avoid while taking CellCept?
•
Avoid pregnancy. See “What is the most important information I
should know about CellCept?”
45
•
Limit the amount of time you spend in sunlight. Avoid using tanning
beds or sunlamps. People who take CellCept have a higher risk of getting
skin cancer. (See “What is the most important information I should
know about CellCept?”) Wear protective clothing when you are in the
sun and use a sunscreen with a high protection factor (SPF 30 and
above). This is especially important if your skin is very fair or if you have
a family history of skin cancer.
What are the possible side effects of CellCept?
CellCept can cause serious side effects:
•
See “What is the most important information I should know about
CellCept?”
•
Low blood cell counts. People taking high doses of CellCept each day
may have a decrease in blood counts, including
• white blood cells, especially neutrophils. Neutrophils fight against
bacterial infections. You have a higher chance of getting an infection
when your white blood cell count is low. This is most common from 3
months to 6 months after your transplant.
• red blood cells. Red blood cells carry oxygen to your body tissues.
You have a higher chance of getting severe anemia when your red
blood cell count is low.
• platelets. Platelets help with blood clotting.
Your doctor will do blood tests before you start taking CellCept and during
treatment with CellCept to check your blood cell counts.
Tell your doctor right away if you have any signs of infection (see “What
is the most important information I should know about
CellCept?”), or any unexpected bruising or bleeding. Also, tell your
doctor if you have unusual tiredness, lack of energy, dizziness or fainting.
•
Stomach problems. Stomach and intestinal bleeding can happen in
people who take high doses of CellCept. Bleeding can be severe and you
may have to be hospitalized for treatment.
Common side effects include:
•
•
•
•
•
•
diarrhea. Call your doctor right away if you have diarrhea. Do not stop
taking CellCept without first talking with your doctor.
vomiting
pain
stomach area pain
swelling of the lower legs, ankles and feet
high blood pressure
46
Side effects that happen more often in children than in adults taking CellCept
include:
•
•
•
•
•
•
•
stomach area pain
fever
infection
pain
blood infection (sepsis)
diarrhea
vomiting
•
•
•
•
•
sore throat
colds (respiratory tract infections)
high blood pressure
low white blood cell count
low red blood cell count
These are not all of the possible side effects of CellCept. Tell your doctor
about any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side
effects to the FDA at 1-800-FDA-1088 or to Genentech at 1-888-835-2555.
How should I store CellCept?
•
Store CellCept capsules and tablets at room temperature, between 59oF
to 86oF (15oC to 30oC). Keep the container closed tightly.
•
Store the prepared CellCept Oral Suspension at room temperature,
between 59oF to 86oF (15oC to 30oC), for up to 60 days. You can also
store CellCept Oral Suspension in the refrigerator at 36oF to 46oF (2oC to
8oC). Do not freeze CellCept Oral Suspension.
•
Keep CellCept and all medicines out of the reach of children
General Information about CellCept
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use CellCept for a condition for which it was not
prescribed. Do not give CellCept to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about
CellCept. If you would like more information, talk with your doctor. You can
ask your doctor or pharmacist for information about CellCept that is written
for healthcare professionals. For more information, call 1-888-835-2555 or
visit www.gene.com/gene/products/information/cellcept.
What are the ingredients in CellCept?
Active Ingredient: mycophenolate mofetil
Inactive Ingredients:
CellCept 250 mg capsules: croscarmellose sodium, magnesium stearate,
povidone (K-90) and pregelatinized starch. The capsule shells contain black
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iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium
lauryl sulfate, titanium dioxide, and yellow iron oxide.
CellCept 500 mg tablets: black iron oxide, croscarmellose sodium, FD&C blue
#2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol 400,
povidone (K-90), red iron oxide, talc, and titanium dioxide; may also contain
ammonium hydroxide, ethyl alcohol, methyl alcohol, n-butyl alcohol,
propylene glycol, and shellac.
CellCept Oral Suspension: aspartame, citric acid anhydrous, colloidal silicon
dioxide, methylparaben, mixed fruit flavor, sodium citrate dihydrate, sorbitol,
soybean lecithin, and xanthan gum.
CellCept Intravenous: polysorbate 80, and citric acid. Sodium hydroxide may
have been used in the manufacture of CellCept Intravenous to adjust the pH.
This Medication Guide has been approved by the US Food and Drug
Administration.
CELLCEPT, CYTOVENE-IV, and VALCYTE are registered trademarks of
Hoffmann-La Roche Inc.
BACTRIM and BACTRIM DS are trademarks of Hoffmann-La Roche Inc.
MG Revised: July 2015
For additional copies of this Medication Guide, please call 1-800-617-8191 or
visit www.gene.com/gene/products/information/cellcept.
© 2015 Genentech, Inc. All rights reserved.
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